1. Field of Invention
The present invention provides novel compounds possessing one or more of the following activities: antibacterial, antifungal, antiviral, anticancer, and antiparasitic activity. Pharmaceutical compositions containing these compounds, methods of making and methods for using these compounds are also provided.
2. State of the Art
Invasive fungal infections are a serious cause of mortality in many patients including an increasing number of immunocompromised patients. Few treatment choices exist and first-line therapies have significant limitations due to safety problem and lack of broad spectrum activity. The growing prevalence of fungal strains resistant to currently available therapies presents an additional clinical challenge. Meanwhile, the rapid emergence of bacterial infections resistant to treatment with standard antibiotics constitutes another serious public health threat. Novel antibacterial and antifungal agents are needed which are less prone to give rise to resistance or are directed towards novel biological targets.
Using small molecule drugs to cause cell death through DNA interaction is a proven approach in treating cancer and microbial infections. Smaller compounds are more likely to have suitable cellular uptake and pharmacokinetic properties compared to higher molecular weight compounds. The binding of the antibacterial netropsin and distamycin to AT-rich sequences in the minor groove of double stranded DNA is a well studied phenomenon. Because such binding can be used to regulate DNA expression, e.g., by blocking and/or displacement of regulatory proteins, or by inhibiting the activity of enzymes acting on DNA, such as reverse transcriptase or topoisomerase, optimization of this binding has been the subject of numerous recent studies.
As described in a review by Bailly and Chaires (Bioconj. Chem. 9(5):513–38, 1998), the pyrrolecarboxamide unit in netropsin and distamycin is actually about 20% longer than required to perfectly match the corresponding base pair sequence in the minor groove. Accordingly, in oligomeric analogs having multiple binding moieties, successive binding moieties can become out of phase with the base pairs of the minor groove. Several studies have therefore been directed to dimers of netropsin or distamycin containing different linkers, in order to improve binding to longer target sequences. In these reports, effectiveness of various netropsin or distamycin dimers was determined, for example, in the inhibition of transcription by HIV-1 reverse transcriptase (M. Filipowsky et al, Biochemistry 35:15397–410, 1996), inhibition of mammalian DNA topoisomerase I (Z. Wang et al., Biochem. Pharmacol. 53:309–16, 1997), or inhibition of HIV 1 integrase (N. Neamati et al., Mol. Pharmacol. 54:280–90, 1998). Preferred linkers in these studies included p-phenylene, trans-vinyl, cyclopropyl, 3,5-pyridyl, and six- and eight-carbon aliphatic chains. Several of these linkers restrict rotation around the linking group, thus reducing the extent of purely monodentate binding (e.g. by only one netropsin moiety; see Bailly) which can occur with flexible linkers. However, Kissinger et al. (Chem. Res. Toxicol. 3(2): 162–8, 1990) reported that aryl-linked groups had reduced DNA binding affinity compared to alkyl and alkylene linkers, and Neamati et al. (cited above) reported that the trans-vinyl linked compound was many times more potent (in inhibiting HIV-1 integrase) than the “more rigid” cyclobutanyl and norbornyl linkers. It was suggested in Wang and in Bailly that, for certain applications, the more rigid linkers (cyclopropyl and p-phenylene) may not allow for optimal simultaneous (bidentate) binding of the two netropsin moieties flanking the linker. Therefore, it would be desirable to provide linkers which reduce monodentate binding but which provide suitable geometries for bidentate binding. Nervertheless, there is much confusion as to what constitutes linkers of choice such that highly effective antibacterial, antifungal and/or anticancer compounds are formed. In light of the foregoing discussion, there is a need to develop new compounds to treat diseases such as cancer, bacterial, fungal and viral infection. The compounds of the present invention fulfill this need.